The present invention relates to the use of derivatives of aryl(or heteroaryl)azolylcarbinols of general formula (I), as well as their physiologically acceptable salts, in the manufacture of medicaments, useful in human and/or veterinary therapy, for the treatment of disorders that are mediated by an excess of substance P, and especially disorders of the central nervous system such as anxiety, depression, schizophrenia, manic depressive psychosis, sexual dysfuntion, drug addiction, cognitive disorders, locomotive disorders, etc.
Substance P is a peptide, a tachykinin, that can be isolated from brain tissue and the gastrointestinal tract. In the brain, substantia nigra and the basal ganglions contain relatively high concentrations of substance P.
There is evidence suggesting that substance P functions as a neurotransmitter. In the basal ganglions, substance P is synthesised in the medium sized striatal neurones with spinae, which project the substantia nigra pars reticulate. Studies on the receptor distribution indicate that the receptors NK1 are found in the striate at a relatively high density, but are to all extents and purposes absent from the substantia nigra. However, the substantia nigra contains one of the highest levels of tissue substance P in the central nervous system. Although this seems to indicate that receptor and ligand are unpaired, substance P can interact with the receptors in the striate by release of from collateral local axons of the striatonigral neurones. The terminals containing substance P have been shown to make synaptic contact with the cholinergic cell bodies in the striate. In the striate, the receptors NK1 seem to be expressed mainly by cholinergic inter-neurones, although a small population of non-cholinergic striatal neurones can also express these receptors. Furthermore, stimulation of the NK1 receptors by substance P has been shown to increase the release of acetylcholin (Ach), both in vitro and in vivo. As a consequence, an anatomical circuit has been described in which substance P, released locally in the striate from the collateral axons of the striatonigral neurones can bind to the NK1 receptors of the striatal cholinergic inter-neurones to stimulate the release of acetylcholine (J. J. Anderson, J.Pharmacol. Exp. Ther., 1995, 274, 928-936).
Substance P has also been implicated in the pathophysiology of several neuropsychiatric disorders such as, schizophrenia, manic depressive psychosis, sexual dysfunction, drug addiction, cognitive disorders, locomotive disorders, or with depression (M. Bianchi, Inflamm. Res., 1995, 44 (11), 466-469). Similarly, a clear relation between depressive states and levels of substance P can be supposed, since the products that act as inhibitors of substance P have a clear anti-depressive component when studied in various laboratory animal models.
On the other hand, there is also a relation between the anxiety processes (anxiolisis/anxiogenesis) with the levels of substance P. It has been demonstrated that products that act as antagonists of the NK1 receptor display anxiolytic activity in a social interaction trial (S. File, Pharmacol. Biochem. Behav., 1997, 58 (3), 747-752), with little tendency towards the development of tolerance. Similarly, administration of substance P is an anxiogenic agent when studied in the elevated-plus-maze trial (R. M. Teixeira, Eur.J. Pharmacol., 1996, 31 (1), 7-14), and substance P receptor blockers have the opposite effect. It can therefore be deduced that the levels of substance P play an important role in the expression of anxiety.
In our patents EP 289380 and ES 9800793 we have described carbinol derivatives of general formula (I) 
wherein Ar represents a benzene ring or a substituted or unsubstituted thiopheno ring, R1 represents a hydrogen atom or a lower alkyl group (C1-C4); R2 represents a dialkylaminoalkyl or azahetercyclylalkyl radical and Het represents an azol, as well as their physiologically acceptable salts, which are claimed for the treatment of pain.
In our patents PCT/EP 96105596, ES 9701538, ES 9701728 and ES 9800793 we have also described several procedures for preparing enantiomerically pure compounds of general formula (I).
We have now discovered that the compound of general formula (I), as well as their physiologically acceptable salts, are especially useful in the manufacture of medicaments, useful in veterinary and/or human therapy, for the treatment of disorders that are mediated by an excess of substance P, especially certain disorders of the central nervous system such as anxiety, depression, schizophrenia, manic depressive psychosis, sexual dysfunction, drug addiction, cognitive disorders, locomotive disorders, etc.
The present invention relates to the use of derivatives of aryl(or Ieteroaryl)azolylcarbinol of general formula (I) 
where
Ar is a phenyl or thienyl radical, unsubstituted or optionally substituted by 1, 2 or 3 identical or different substituents, selected from the group composed of fluorine, chlorine, bromine, methyl, trifluoromethyl and methoxy;
R1 is a hydrogen atom, a cyclohexyl group, an N-methylpiperidyl group, a phenyl group, a vinyl group or a C1-C4 alkyl group;
R2 is a hydrogen atom or di(C1-C4 alkyl)amino (C2-C3 alkyl), (C1-C2 alkyl)azaheterocyclyl (C2-C3 alkyl), or azaheterocyclyl (C2-C3 alkyl); and
Het is a heterocyclic azotic five-membered ring that contains from one to three nitrogen atoms, unsubstituted or optionally substituted by 1 or 2 identical or different substituents selected from the group composed of fluorine, chlorine, bromine, a C1-C12 alkyl group, a benzyl radical, a cyano C2-C3alkyl) radical, a carboxyalkyl (C2-C3 alkyl) radical, a methoxycarbonyl (C2-C3 alkyl) radical, a hydroxy (C2-C3 alkyl) radical, an amino (C2-C3 alkyl) radical, a di(C1-C4 alkyl)amino (C2-C3 alkyl) radical and an azaheterocyclyl (C2-C3 alkyl) radical; or one of its physiologically acceptable salts, in the manufacture of a medicament for the treatment of disorders that are produced by an excess of substance P, and specially disorders of the central nervous system involving substance P receptors such as anxiety, depression, schizophrenia, manic depressive psychosis, sexual dysfuntion, drug dependency, cognitive disorders, locomotive disorders, etc., in mammals, including man.
The term xe2x80x9cC1-C4 alkyl groupxe2x80x9d represents a straight or branched radical that is derived from a saturated hydrocarbon of from 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and terc-butyl for example.
The term xe2x80x9cdi(C1-C4 alkyl)amino (C2-C3 alkyl), (C1-C2 alkyl)azaheterocyclyl (C2-C3 alkyl), or azaheterocyclyl (C2-C3 alkyl)xe2x80x9d represents an alkyl radical of two or three carbon atoms joined to a diC1-C4 alkyl)amine or to a (C1-C2 alkyl)azaheterocycle or to an azaheterocycle, respectively, such as dimethylaminoethyl, dimethylaminopropyl, diethylaminoethyl, piperidylethyl, N-ethylpiperidylethyl, N-methylpyrrolidinylethyl, morpholinylpropyl, pyrrolidinylalkyl, etc.
The term xe2x80x9ccyano (C2-C3 alkyl)xe2x80x9d represents an alkyl radical of two or three carbon atoms joined to a cyano functional group.
The term xe2x80x9ccarboxy(C2-C3 alkyl)xe2x80x9d represents an alkyl radical of two or three carbon atoms joined to a carboxyl functional group.
The term xe2x80x9cmethoxycarbonyl(C2-C3 alkyl)xe2x80x9d represents an alkyl radical of two or three carbon atoms joined to a methoxycarbonyl functional group.
The term xe2x80x9chydroxy(C2-C3 alkyl)xe2x80x9d represents an alkyl radical of two or three carbon atoms joined to a hydroxyl functional group.
The term xe2x80x9camino(C2-C3 alkyl)xe2x80x9d represents an alkyl radical of two or three carbon atoms joined to an amino functional group.
The compounds of general formula (I) can be synthesised according to the procedures described in patents EP 289380 or ES 9800793. The compounds of general formula (I) have a stereogenic centre and the invention relates both to the use of a pure enantiomer and to a mixture of enantiomers. The enantiomers can be prepared by some of the procedures described in our patents PCT/EP 96/05596, ES 9701538, ES 9701728 or ES 9800793.
Examples of pharmaceutical compositions that contain compounds of general formula (I) are described in our patents EP 289380 or ES 9800793.
Illustrative examples of the compounds provided in the present invention include the compounds that are characterised by the data presented in tables 1 to 7.
In the present invention the activity of the compounds of general formula (I) has been demonstrated experimentally in the claimed applications, by means of a study of the in vivo effect on the release of substance P and also in two in vivo trials of anti-depressive activity.